Diapositiva 1

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La preparazione alla PTCA nelle SCA
Roma 20 Marzo 2010
Preparazione farmacologica alla PTCA dalle linee
guida ai dati degli studi e dei registri Negli
Ospedali con emodinamica
Gavino Casu Cardiologia-Nuoro.
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Hospital Mortality
10 8 6 4 2 0
Death in hospital
STEMI
NSTEMI
UA
dead
60
25-30
Mid 1980
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0 1 2 3 4
5 6 7 8 9
10
Days
4-6
Armstrong. JAMA 2007 ASSENT -4 PCI study. Lancet
2006 GRACE Study. BMJ 2006
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PCI capable Hospital
Primary PCI
Rescue PCI
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Mortality benefit from primary PCI
Risk profile
Time (PCI-related delay time)
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Improve myocardial reperfusion
1)   A shorter delay for access to hospital care
(Call-to-door time) 2)   Hospitals capable of
performing primary PCI 24/7 3)   Experienced
teams capable of using the latest techniques such
as thrombus extraction, and optimal antiplatelet
and antithombotic therapy
Jean Fajadet
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re-occlusion, distal embolization, stent
thrombosis
In-ospital bleeding
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Antithrombotic Options
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Adjuctive antithrombotic Treatment
ASPIRIN
- Aspirin should be given to all patients with
STEMI as soon as possible
IB
Started dose 150-325 mg in chewable form/250-500
mg iv. A lower dose (75-160 mg) is given orally
daily thereafter for life.
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Adjuctive antithrombotic Treatment
Use of Thienopyridines in Percutaneous Coronary
Intervention

• preventing post-PCI-related complications
• preventing coronary stent subacute
  thrombosis
• preventing thrombotic events in native
  coronary vessels.

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Adjuctive antithrombotic Treatment
ThienopyrydinesCLOPIDOGREL
- Clopidogrel should be given as soon as possible
to all patients with STEMI undergoing PCI
IC
Loading dose 300/600 mg. Daily dose of 75 mg
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Primary outcome of cardiovascular death, MI, or
urgent target-vessel revascularization at 30 days
after percutaneous coronary intervention and
clopidogrel.
0,8 0,6 0,4 0,2 0
placebo
clopidogrel
Cumulative hazard rates
P0,03
0 5 10
15 20
25 30
The PCI-CURE trial. Mehta SR et al
Days of folllow-up
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The PCI-CLARITY trial
Major cardiovascular outcomes No. Outcome
Clopidogrel pretreatment No
pretreatment Adjusted odds ratio
p-value (n933)
(n930) (95 CI) Outcomes
before PCI 37 (4)
58 (6,2) 0,62
(0,40-0,95) 0,03
Sabatine. CLARITY Study. N. Engl J Med
2005 Sabatine. PCI CLARITY. JAMA 2005
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Effect of Pretreatment With Clopidogrel on
Early Reperfusion and Adverse Event Rates in
Univariate-Weighted Logistic Regression Analysis

Unadjusted Treatment Effect Unadjusted Treatment Effect Unadjusted Treatment Effect
OR 95 CI P
TIMI grade 2/3 flow 1.53 1.391.68 lt0.0001
Mortality 0.52 0.410.67 lt0.0001
Death/reinfarction 0.50 0.400.62 lt0.0001

OR is for the occurrence of TIMI grade 2/3 flow, mortality, and death/reinfarction for pretreatment with clopidogrel. OR is for the occurrence of TIMI grade 2/3 flow, mortality, and death/reinfarction for pretreatment with clopidogrel. OR is for the occurrence of TIMI grade 2/3 flow, mortality, and death/reinfarction for pretreatment with clopidogrel. OR is for the occurrence of TIMI grade 2/3 flow, mortality, and death/reinfarction for pretreatment with clopidogrel.
Vlaar. Circulation. 2008
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Clopidogrel loading dose 300 vs 600 mg
100
Ticlopidine 2x 500mg, then 250mg BID Clopidogrel
300mg, then 75mg QDClopidogrel 600mg, then 75mg
BID
60
of 20µM ADP-induced aggregation
20
0
0
4
24
48
Time after Administration (hours)
Muller I et al. Heart 20018592-93
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CURRENT-OASIS 7 a randomized, 2 x 2 factorial
trial evaluating optimal dosing strategies for
clopidogrel and aspirin in patients with ST and
non-ST-elevation acute coronary syndromes managed
with an early invasive strategy.
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CURRENT OASIS-7 Benefit to doubling clopidogrel
dose in ACS patients undergoing PCI
Clopidogrel
300/75 mg
600/150mg
-15 cardiovascular, death, MI, stroke -22 risk
of MI -42 risk stent thrombosis
ESC 2009
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Double vs standard dose of clopidogrel Primary
outcome and components
Measure Standard clopidogrel therapy Double clopidogrel therapy Hazard ratio (95 CI)
Cardiovascular death, MI, and stroke, overall cohort (n25 087) 4.4 4.2 0.95 (0.841.07)
PCI cohort (n17 232) 4.5 3.9 0.85(0.740.99)
No PCI cohort (n7855) 4.2 4.9 1.17 (0.951.44)
MI, overall cohort 2.2 1.9 0.86 (0.731.03)
PCI cohort 2.6 2.0 0.78 (0.640.95)
No PCI cohort 1.4 1.7 1.25 (0.871.79)
Mehta S. European Society of Cardiology 2009
Congress August 30, 2009 Barcelona, Spain.
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Double vs standard dose of clopidogrel Primary
outcome and components
Measure Standard clopidogrel therapy Double clopidogrel therapy Hazard ratio (95 CI)
Cardiovascular death, overall cohort 2.2 2.1 0.96 (0.811.14)
PCI cohort 1.9 1.9 0.96 (0.771.19)
No PCI cohort 2.8 2.7 0.96 (0.741.26)
Stroke, overall cohort 0.5 0.5 0.99 (0.701.39)
PCI cohort 0.4 0.4 0.88 (0.551.41)
No PCI cohort 0.8 0.9 1.11 (0.681.82)
Mehta S. European Society of Cardiology 2009
Congress August 30, 2009 Barcelona, Spain.
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Bleeding outcome and stent thrombosis in PCI
population
Outcome Standard clopidogrel therapy (n8684) Double clopidogrel therapy (n8548) Hazard ratio (95 CI)
Definite stent thrombosis 1.2 0.7 0.58 (0.420.79)
TIMI major bleeding 0.5 0.5 1.06 (0.701.61)
CURRENT major bleeding 1.1 1.6 1.44 (1.111.86)
CURRENT severe bleeding 0.8 1.1 1.39 (1.021.90)
Fatal bleeding 0.15 0.07 0.47 (0.181.23)
ICH 0.035 0.046 1.35 (0.306.04)
Red blood cell transfusion gt2U 0.91 1.35 1.49 (1.111.98)
CABG-related major bleeding 0.1 0.1 1.69 (0.614.7)
Mehta S. European Society of Cardiology 2009
Congress August 30, 2009 Barcelona, Spain.
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Results of the aspirin dose comparison Efficacy
and bleeding
Measure Aspirin 75100 mg Aspirin 300325 mg Hazard ratio (95 CI)
Cardiovascular death, MI, and stroke (n25 087) 4.4 4.2 0.96 (0.851.08)
PCI cohort (n17 232) 4.2 4.1 0.98 (0.841.13)
No PCI cohort (n7855) 4.7 4.4 0.92 (0.751.14)
Stent thrombosis 2.1 1.9 0.91 (0.731.12)
TIMI major bleed 1.03 0.97 0.94 (0.731.21)
CURRENT major bleed 2.3 2.3 0.99 (0.841.17)
CURRENT severe bleed 1.7 1.7 1.00 (0.831.21)
Mehta S. European Society of Cardiology 2009
Congress August 30, 2009 Barcelona, Spain.
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Clopidogrel limitations

• Slow onset
• Low level of inhibition
• Too much variability

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Prasugrel
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TRITON-TIMI 38
TRITON allowed recruitment of STEMI patients
undergoing primary PCI when they presented lt 12
hours of symptom onset or secondary PCI when they
presented late
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Primary EP (CV death, MI and stroke at 15
months)
Montalescot Lancet 2009
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Key secondary EP (CV death, MI, and UTVR at 30
days)
Montalescot Lancet 2009
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Stent thrombosisARC Definite/probable
HR0.58 (0.360.93) NNT83
Montalescot Lancet 2009
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TIMI major non-CABG bleeding
HR1.11 (0.701.77) NNH333
Age-adjusted HR1.19 (0.75-1.89)
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Conclusions In STEMI patients undergoing PCI

• Prasugrel was superior to standard dose
  clopidogrel to prevent ischaemic events
• Prasugrel did not have more bleeding events
  compared to those who were treated with
  clopidogrel, and this was equally true for
• Primary PCI
• Secondary PCI
• Major bleeding
• Minor bleeding
• These data make prasugrel an especially
  attractive alternative to clopidogrel in PCI for
  STEMI

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Non-Thienopyridines , reversible P2Y12 inhibitors
Cangrelor
Ticagrelor
CHAMPION program study
PLATO
14.000 pts
18.000 pts
Lack of efficacy
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Comparison of ticagrelor with clopidogrel in
patients with a planned invasive strategy for
acute coronary syndromes (PLATO) a randomised
double-blind study
13
12
10.65
Clopidogrel
11
10
8,95
9
Ticagrelor
8
7
Cumulative incidence ()
6
5
4
3
Cardiovascular death, myocardial infarction,
stroke
2
1
0
0
60
120
180
240
300
360
Days after randomisation
PLATO investigator. Lancet 2010
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PLATO
15
Ticagrelor
11.6
11.5
10
Clopidogrel
K-M estimated rate ( per year)
5
Time of total major bleeding
0
0
60
120
180
240
300
360
Time after randomizzation (days)
PLATO investigator. Lancet 2010
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GIIb/IIIa inhibitors
Death, MI, TVR ()
IIaA
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Periprocedural administration of abiciximab
Better myocardial perfusion
Neumann.Circulation 1998
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30-day FU 7 Studies
6-12 months FU 6 Studies
Abiciximab 30 day FU 5 Studies
Small molecules 30-day FU 4 Studies
30-day FU 6 Studies
De luca. JAMA 2005
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TIROFIBAN
In On-TIME 2 trial pre-hospital initiation of
high-bolus dose tirofiban in association with
aspirin, clopidogrel (600 mg) and heparin
improved ST-segment resolution but was not
associated with more patency of the infarct
vessel or a significant net clinical benefit when
compared wit placebo.
IIbB
Vant Hof. Lancet 2008
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Heparin
i.v. bolus 100 U/kg weigt (60 UI/kg is GPIIb/IIIa
antagonist are used)
IC
ACT 250-300 s (200-250 if GPIIb/IIIa)
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Percutaneous Coronary Intervention in Patients
Receiving Enoxaparin or Unfractionated Heparin
After Fibrinolytic Therapy for ST-Segment
Elevation Myocardial Infarction in the
ExTRACT-TIMI 25 Trial
15 10 5 0
13,8
10,7
Death or MI ()
Death or recurrent MI
0 120 240 360 480
600 720
Hours
ENOX
UFH
Gibson JACC 2007
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A potential role of Enoxaparin
STUDY N DOSE Labeque 143 0,5mg/kg IV 1,0
mg/kg SC SWEDES 205 0,75mg/kg IV
- WEST 304 1,0 mg/kg SC - 1,0
mg/kg SC 0,3-0,5 mg/kg IV
Christy.J Invasiv Cardiol 2008
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Bivaluridin
Direct thrombin inhibitor
Clot-bound
Fluid-phase
Does not activate platelets
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HORIZON-AMI
Control (heparin plus GPI)
22 20 18 16 14 12 10 8 6 4 2 0
Bivaluridin
18,3
15,6
NACE ()
NACE major bleeding or composite major adverse
cardiovascular events
0 1 2 3 4
5 6 7 8 9
10 11 12
Time (month)
Mehran. HORIZON-AMI Trial. Lancet 2009
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12 11 10 9 8 7 6 5 4 3 2 1 0
9,2
Control
5,8
Major bleeding events
Bivaluridin
0 1 2 3 4 5
6 7 8 9 10 11
12
11,9
12 11 10 9 8 7 6 5 4 3 2 1 0
11,9
MACE ()
MACE death, reinfarction, target vessel
revaculariisation or stroke
0 1 2 3 4 5
6 7 8 9 10 11
12
Mehran. HORIZON-AMI Trial. Lancet 2009
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HORIZON-AMI
6 5 4 3 2 1 0
Control
4,8
Bivaluridin
3,5
All-cause mortality ()
0 1 2 3 4
5 6 7 8 9
10 11 12
Mehran. HORIZON-AMI Trial. Lancet 2009
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So.

• Heparin
• GIIb/IIIa inhibitors
• Aspirin
• Loading dose of Clopidogrel

• LMWH?
• GIIb/IIIa inhibitors
• Aspirin
• Loading dose of Clopidogrel

Abiciximab provides an additional benefit to
STEMI patients who receive an optimal Clopidogrel
treatment prior PCI?
Bivaluridin can replace the use of GIIb/IIIa! So
GIIb/IIIa could be used as the bail-out strategy
Prasugrel
Ticagrelor
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